To compare the late neuropsychologic toxicities of CNS prophylaxis in childhood acute lymphoblastic leukemia (ALL), a transversal assessment was performed in two groups of ALL patients and two control groups. The ALL patients had received one of the following CNS prophylaxes: cranial irradiation, 24 Gy and i.t. MTX 10 mg/m2, 6 doses (RT group, n = 25) or i.t. Ara-C 30 mg/m2 and i.t. MTX 10 mg/m2, 10 doses (ChT group, n = 29). The two control groups were: Siblings (Sb, n = 24) and Solid Tumors (ST, n = 22). Intelligence Quotient (IQ), memory, learning, attention and frontal tasks were studied. Comparative analyses between ChT and RT showed no differences in any of the tests. When RT was compared with ST or Sb, RT showed a 10-point lower mean IQ (p greater than 0.05). The results of ChT versus ST or versus Sb were worse in the ChT group. In many tests the differences were statistically significant. Analyses of the 54 ALL patients compared with the 46 controls showed significant differences in all tests except verbal memory and verbal learning. Neuropsychological sequelae of CNS prophylaxis are discussed, and in particular, the role of cranial radiotherapy and i.t. Ara-C. We conclude that prophylactic CNS therapy may cause cognitive dysfunctions.